Half-life is a significant pharmacokinetic parameter included in the excretion phase of absorption, distribution, metabolism, and excretion. It is one of the key factors for the successful marketing of drug candidates. Therefore, predicting half-life is of great significance in drug design. In this study, we employed eXtreme Gradient Boosting (XGboost), randomForest (RF), gradient boosting machine (GBM), and supporting vector machine (SVM) to build quantitative structure-activity relationship (QSAR) models on 3512 compounds and evaluated model performance by using root-mean-square error (RMSE), R2, and mean absolute error (MAE) metrics and interpreted features by SHapley Additive exPlanation (SHAP). Furthermore, we developed consensus models through integrating four individual models and validated their performance using a Y-randomization test and applicability domain analysis. Finally, matched molecular pair analysis was used to extract the transformation rules. Our results revealed that XGboost outperformed other individual models (RMSE = 0.176, R2 = 0.845, MAE = 0.141). The consensus model integrating all four models continued to enhance prediction performance (RMSE = 0.172, R2 = 0.856, MAE = 0.138). We evaluated the reliability, robustness, and generalization ability via Y-randomization test and applicability domain analysis. Meanwhile, we utilized SHAP to interpret features and employed matched molecular pair analysis to extract chemical transformation rules that provide suggestions for optimizing drug structure. In conclusion, we believe that the consensus model developed in this study serve as a reliable tool to evaluate half-life in drug discovery, and the chemical transformation rules concluded in this study could provide valuable suggestions in drug discovery.

This report contains the updated consensus recommendations for optimal hemophilia care produced in 2019 by three Working Groups (WG) on behalf of the European Directorate for Quality of Medicines and Healthcare in the frame of the Kreuth V Initiative. WG1 recommended access to prophylaxis for all patients, the achievement of plasma factor trough levels of at least 3-5% when extended half-life factor VIII (FVIII) and FIX products are used, a personalized treatment regimen, and a choice of chromogenic assays for treatment monitoring. It was also emphasized that innovative therapies should be supervised by hemophilia comprehensive care centers. WG2 recommended mandatory collection of postmarketing data to assure the long-term safety and efficacy of new hemophilia therapies, the establishment of national patient registries including the core data recommended by the European Medicines Agency and the International Society on Thrombosis and Haemostasis, with adequate support under public control, and greater collaboration to facilitate a comprehensive data evaluation throughout Europe. WG3 discussed methodological aspects of hemophilia care in the context of access decisions, particularly for innovative therapies, and recommended that clinical studies should be designed to provide the quality of evidence needed by regulatory authorities, HTA bodies and healthcare providers. The dialogue between all stakeholders in hemophilia care and patient organizations should be fostered to implement these recommendations.

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The purpose of this paper is to summarize the University of Florida Department of Radiation Oncology guidelines for treatment of differentiated thyroid cancer with I-131 or external-beam radiotherapy. This article is not meant to compete with the many excellent book chapters and consensus guidelines that present comprehensive discussions of treatment options. This is a streamlined, \"How we do it?\" reference without substantial discussion of background or supporting data. To serve as a treatment reference, the great majority of the information is presented in topic-specific tables.

Thermostable variants of the Cellulomonas sp. NT3060 glycerol kinase have been constructed by through the introduction of ancestral-consensus mutations. We produced seven mutants, each having an ancestral-consensus amino acid residue that might be present in the common ancestors of both bacteria and of archaea, and that appeared most frequently at the position of 17 glycerol kinase sequences in the multiple sequence alignment. The thermal stabilities of the resulting mutants were assessed by determining their melting temperatures (Tm), which was defined as the temperature at which 50% of the initial catalytic activity is lost after 15 min of incubation, as well as when the half-life of the catalytic activity occurs at a temperature of 60°C (t1/2). Three mutants showed increased stabilities compared to the wild-type protein. We then produced five more mutants with multiple amino acid substitutions. Some of the resulting mutants showed thermal stabilities much greater than those expected given the stabilities of the respective mutants with single mutations. Therefore, the effects of mutations are not always simply additive and some amino acid substitutions, which do not affect or only slightly improve stability when individually introduced into the protein, show substantial stabilizing effects in combination with other mutations.

In recent years, assay levels of natriuretic peptides are used in everyday clinical practice. The most commonly used is the assay the concentration of NT-proBNP in conjunction with the longest half-life (120 minutes) and its stability. According to the guidelines of the European Society of Cardiology determination of NT-proBNP were used in the diagnosis of acute and chronic heart failure, risk stratification in acute coronary syndromes, pulmonary embolism and in assessing the overall risk of cardiovascular patients prior to surgery. In addition, there are works whose authors have demonstrated the usefulness of NT-proBNP determination in valvular, atrial fibrillation, and syncope.

BACKGROUND: Concerns regarding increasing microbial resistance to vancomycin have resulted in recommendations for a higher trough serum vancomycin concentration. This study aimed to assess the dosage guidelines targeting vancomycin trough concentrations of 15-20 mg/L.
METHODS: About 216 adult patients (age, >60 yr) were treated with intravenous vancomycin. The patients were divided into 2 groups according to their target vancomycin trough concentrations: the previous guideline group (n=108) treated with targeted vancomycin trough concentrations of 5-15 mg/L from Jan 2009 through April 2011 and the new guideline group (n=108) treated with targeted concentrations of 15-20 mg/L from November 2011 through July 2012.
RESULTS: The 2 groups were not significantly different with respect to age, weight, initial serum creatinine, initial creatinine clearance, predictive trough levels, doses, serum drug concentrations, and area under the curve/minimal inhibitory concentrations. Regarding the proportions of vancomycin trough concentrations, the target range was achieved in 50% in the previous guideline group and in 16% in the new guideline group. In the previous and new guideline groups, the trough concentrations of 10-20 mg/dL were observed in 32.4% and 52.8% patients, respectively, and those of <10 mg/L were observed in 45.4% and 29.6%, respectively.
CONCLUSIONS: Compared to the previous guideline group, the new guideline group showed higher proportions in the therapeutic range of 10-20 mg/L and lower proportions in trough concentrations <10 mg/L. The strictly managed vancomycin therapeutic drug monitoring in the new guideline group was assessed as more effective.

Bioaccumulation in fish is a function of competing rates of chemical uptake and elimination. For hydrophobic organic chemicals bioconcentration, bioaccumulation and biomagnification potential are high and the biotransformation rate constant is a key parameter. Few measured biotransformation rate constant data are available compared to the number of chemicals that are being evaluated for bioaccumulation hazard and for exposure and risk assessment. Three new Quantitative Structure-Activity Relationships (QSARs) for predicting whole body biotransformation half-lives (HLN) in fish were developed and validated using theoretical molecular descriptors that seek to capture structural characteristics of the whole molecule and three data set splitting schemes. The new QSARs were developed using a minimal number of theoretical descriptors (n=9) and compared to existing QSARs developed using fragment contribution methods that include up to 59 descriptors. The predictive statistics of the models are similar thus further corroborating the predictive performance of the different QSARs; Q(2)ext ranges from 0.75 to 0.77, CCCext ranges from 0.86 to 0.87, RMSE in prediction ranges from 0.56 to 0.58. The new QSARs provide additional mechanistic insights into the biotransformation capacity of organic chemicals in fish by including whole molecule descriptors and they also include information on the domain of applicability for the chemical of interest. Advantages of consensus modeling for improving overall prediction and minimizing false negative errors in chemical screening assessments, for identifying potential sources of residual error in the empirical HLN database, and for identifying structural features that are not well represented in the HLN dataset to prioritize future testing needs are illustrated.

BACKGROUND: The increase in forced expiratory volume in one second (FEV1) effected by a bronchodilator is routinely assessed when patients undertake pulmonary function testing (PFT). Several drug classes can theoretically affect the magnitude of the increase in FEV1. Withholding periods are advised for many but not all such drugs. Anecdotally, many subjects presenting for PFT are found to have taken drugs that might affect the test. We did an audit of patients presenting for PFT to assess the frequency with which FEV1 reversibility might be affected by drugs.
METHODS: One hundred subjects presenting to the laboratory for PFT were questioned about recent drug consumption by an independent pharmacy intern. Reversibility of FEV1 was assumed to have been affected if drugs of interest were consumed within defined withholding periods or two half-lives for drugs without such data.
RESULTS: Sixty-three subjects were prescribed drugs likely to affect FEV1 reversibility. Thirty-six subjects consumed at least one such drug within the withholding period. Half (18) of these patients consumed β-blockers with or without β-agonists. Sixty-five subjects did not recall receiving any advice about withholding drugs prior to the test and only 10 recalled receiving advice from their clinician or pulmonary function technician.
CONCLUSIONS: Subjects presenting for PFT are infrequently advised to withhold drugs that may affect FEV1 reversibility, and consequently, often take such drugs close to the time of the test. Therefore, it is likely that the increase in FEV1 is frequently affected by interference from drugs and this might impact on diagnosis and/or treatment options.

Since its approval, fluoroquinolones have become one of the most prescribed antibacterial agents. Because of its widespread use, serious concerns about the emergence of resistance in Streptococcus pneumoniae, Pseudomonas spp, and entrobacteriaceae, has arisen, especially because of cross-resistance between fluoroquinolones. Huge efforts has been done to identify pharmacokinetic (PK) parameters like maximum serum concentration (Cmax), area under the curve of serum concentrations (AUC) and pharmacodynamic (PD) parameters like the minimum inhibitory concentration (MIC) or the mutant prevention concentration (MPC), to optimize the use of the new fluoroquinolones, especially against these difficult to treat microorganisms. The new fluoroquinolones commercially available in Spain, levofloxacin and moxifloxacin, have significant differences in their PK (Cmax, half-life, volume of distribution, etc), PD (MIC, MPC,) and in their PK/PD parameters (AUC/MIC; AUC/MPC) that allow clinicians to establish clear preference for the utilization of one of them. Proper use of these new fluoroquinolones according to these PK/PD parameters will result in better management of respiratory infections with a reduction in the emergence of resistance. Based on data reviewed in this paper moxifloxacin use, with best PK/PD characteristics, should be preferred over levofloxacin. Should levofloxacin be used, alternative dosing strategies would be recommended to avoid selection of resistant variants.